Vector calculations applied to decision matrix to conduct anesthetic level titration

Abstract

Method for controlling the hypnotic and analgesic concentration of anesthetic compositions, the method comprising the steps of: providing a memory unit configured to receive and record data; providing at least one data processing unit (101) in signal communication with the memory unit and configured to process data and record the same in the memory unit; providing a patient treated with a first anesthetic composition comprising an initial hypnotic concentration and an initial analgesic concentration, and recording the patient's bispectral index (P BIS ) and mean arterial pressure (P MAP ), and storing the patient's P BIS and P MAP data in the memory unit, the method being characterized in that it further comprises the steps of: providing a two-dimensional matrix defined on the abscissa by a MAP dimension varying with respect to the mean arterial pressure and on the ordinate by a BIS dimension varying with respect to the bispectral index; defining in the matrix an optimal anesthesia zone (OAZ) located at MAP values of 65 to 110 mmHg and BIS values of 40 to 60; locating in the matrix the values of P BIS and P MAP data to define in the matrix the patient's position (B) with respect to the optimal anesthesia zone (OAZ); providing an algorithm resident in the processing unit configured to quantify the deviation of the patient's position (B) with respect to the optimal anesthesia zone (OAZ) and transform the deviation into a quantitative change in the initial hypnotic concentration and / or the initial analgesic concentration of the first anesthetic composition to define a target hypnotic concentration and / or a target analgesic concentration of a second anesthetic composition; processing the patient's P BIS and P MAP data using the algorithm to obtain the target hypnotic concentration and / or the target analgesic concentration of the second anesthetic composition.

Description

TECHNICAL FIELD

[0001] The present invention relates to a method for controlling the concentration of drugs used in anesthesia. In particular, the method of the present invention implements a series of steps that enable the optimization of the adjustment of the anesthetic concentration for the induction and maintenance of balanced anesthesia and the stop of anesthesia in the wake-up step. BACKGROUND

[0002] General anesthesia mainly comprises two components: hypnosis and control of the stress response to surgical trauma; in this sense, anesthesia can be maintained through the systemic administration of a hypnotic and an analgesic, so that the therapeutic purposes of anesthesia are achieved through the combined action of the two drugs 1,2 . This technique of anesthesia is commonly referred to as "balanced anesthesia".

[0003] Both the hypnotic and the analgesic contribute at least partially to obtaining the two components of anesthesia and interact synergistically with each other to produce the anesthetized state 3,4,5 . The synergistic interaction enables the use of lower doses of each drug to achieve balanced anesthesia, potentially reducing the occurrence of side effects. Several studies have been designed to identify the optimal concentrations of hypnotic and opioid combinations suitable for ensuring adequate anesthesia, ensuring the lowest exposure of the patient to the anesthetics.

[0004] One of the problems that remains unsolved in this clinical scenario concerns the method applied to adjust the level of anesthesia whenever the selected target concentration is not suitable for controlling the patient's response to the procedure-related stress during the induction, maintenance and wake-up steps. In order to control the level of balanced anesthesia, it is necessary to answer two questions: which drug needs to be adjusted and how its concentration needs to be adjusted.

[0005] The mathematical model that describes the pharmacodynamic interaction between analgesics and hypnotics makes it possible to identify an infinite combination of concentrations that produce the same effect, so that different titration strategies can be practiced when the patient deviates from the optimal anesthetized state.

[0006] Figure 1 The method taken by the anesthetist over time is illustrated, which is consistent with the methods disclosed in the literature and introduced in clinical practice: studies of the synergistic action of hypnotics and opioids have shown that a certain level of anesthesia, measured as the level of response to an increased stress stimulus or the intensity of hypnosis, can be obtained by using (X) high concentrations of hypnotics and low concentrations of opioids, (Y) low concentrations of both, (Z) minimum concentrations of hypnotics and high concentrations of opioids.

[0007] For the same reason, the separate monitoring of the different pharmacodynamic signals of the two drugs does not solve the dilemma.

[0008] Alternative methods include the combination in a matrix of vital parameters for identifying the level of hypnotic or stress response, such as the method proposed by G.M. Gurman in the publication of 1994 6 Figure 2 ). This matrix is based on the electroencephalogram and blood pressure signals as control variables; for both parameters, it is possible to define a range of values that identify the optimal anesthetic region.

[0009] With regard to this region, Gurman identifies nine different clinical conditions in response to the planning of an increase or decrease in one or the other of the anesthetics, which are characterized by a suitable increase or suitable decrease in the combination of one or both vital parameters.

[0010] Problems of the background art

[0011] The Gurman matrix makes it possible to consider the vital parameters of the patient to understand which drug to intervene on to balance the anesthesia, but does not indicate how to intervene on the hypnotic and / or analgesic concentration to obtain a balanced anesthesia.

[0012] The existing technical methods for adjusting the hypnotic and analgesic concentration during anesthesia are based on the experience of the anesthetist and on unstructured methods, which lead to an uncoordinated management of the patient. SUMMARY

[0013] The Applicant has now discovered that it is possible to solve the problems of the known art by introducing a vector calculation that quantifies the deviation induced in the patient from the values expected according to a balanced anesthesia, and transforms this degree of deviation into a balanced intervention on the hypnotic and analgesic concentration by means of an algorithm.

[0014] In particular, it is an object of the present invention to provide a method for controlling the concentration of the drugs used in anesthesia, so as to facilitate the selection of the parameters to be modified to optimize the steps of inducing and maintaining a balanced anesthesia and the awakening step.

[0015] The technical task and the specific objects mentioned are substantially achieved by a method for controlling the concentration of the hypnotic and anesthetic drugs of an anesthetic composition, comprising the technical characteristics set out in one or more of the attached claims.

[0016] Advantages of the invention

[0017] The method of the present invention advantageously makes it possible to combine several anesthetic-related variables together in a single matrix, working towards the purpose of balancing the anesthesia.

[0018] Unlike the Gurman matrix, the method of the present invention not only makes it possible to decide which drug to intervene on, but also to quantify the intervention on the concentration of the anesthetics, thus adjusting the adaptability of the anesthesia plan. ​

[0019] Advantageously, the method is based on a single algorithm able to simultaneously manage the hypnotic and analgesic components of the anaesthesia.

[0020] As previously mentioned, the adjustment of the hypnotic and analgesic concentrations during anaesthesia is currently based on the clinical experience of the anaesthetist, since there is no standardised method for the treatment of the patient. This is partly due to the fact that, since the individual pharmacological agents (hypnotic and analgesic) independently contribute to maintaining the first pharmacological effect and to maintaining the second pharmacological effect, the use of a combination of hypnotic and analgesic does not enable the hypnotic effect to be controlled independently of the analgesic effect. In fact, a synergistic effect between hypnotic and analgesic is believed to exist; in practice, this synergistic effect greatly complicates the work of the anaesthetist who, by trial and error, formulates the anaesthesia plan.

[0021] In this sense, it is very advantageous to use a single algorithm to process the clinical indicators relating to both the hypnotic state and the analgesic state of the patient and to return a general parameter (identified hereinafter as D%) applicable to the increase / decrease calculation of both the hypnotic and analgesic concentrations, not only for the simplicity of the calculation, but also because this manages to integrate both the hypnotic and sedative components into a vector calculation. This enables the anaesthesia level to be monitored as a unitary condition, considering two variables which in the prior art should be analysed separately, but which are related and influence each other from a pharmacological point of view.

[0022] The method of the present invention aims to standardise the administration of anaesthetic drugs without including any hypothesis on the mechanisms involved in the patient's reaction to stress stimuli and anaesthesia by the anaesthetist.

[0023] The present method enables a step-by-step intervention on the patient according to a unified algorithm which manages the patient; all patients can be managed optimally, regardless of the experience or fatigue of the anaesthetist. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 : diagram of the different pharmacological strategies for generating balanced anaesthesia according to hypnotic and analgesic concentrations as follows: (X) high hypnotic concentration and low analgesic concentration, (Z) low hypnotic concentration and high analgesic concentration, or (Y) low concentration of both.

[0025] Figure 2 : matrix proposed by Gurman in 1994 which combines the spectral edge frequency (SEF) of the electroencephalogram with the blood pressure (BP) to monitor the depth of anaesthesia.

[0026] Figure 3: Preferred embodiment of the matrix for the purpose of the method of the present application. The matrix is obtained by the intersection of the dimension MAP on the abscissa and the dimension BIS on the ordinate. MAP varies from 0 to 150 mmHg and BIS varies from 0 to 100. The optimal anesthesia zone (OAZ) is defined by a BIS value of 40 to 60 and a MAP value of 65 to 85 mmHg.

[0027] Figure 4 : Schematic representation of the sub-step for quantifying the deviation of the patient position (B) with respect to the point (A) of the optimal anesthesia zone (OAZ) by means of vector analysis.

[0028] Figure 5 : Schematic representation of the sub-step for calculating the increase or decrease of the initial hypnotic and / or anesthetic concentration.

[0029] Figure 6 : Schematic representation of the clinical case reported in Example 2.

[0030] Figure 7 : Schematic representation of the preferred embodiment for the purpose of the method of the present application.

[0031] Figure 8 : Display example of the graphical interface of the computer program configured to implement the steps of the method of the present application. DETAILED DESCRIPTION

[0032] The present application relates to a method for controlling the hypnotic and analgesic concentration of an anesthetic composition, comprising the following steps.

[0033] The method comprises a step for providing at least one memory unit configured to receive and store data. Preferably, the memory unit is provided with a plurality of memory areas in which the data received by the data processing unit are stored.

[0034] The method comprises a step for providing at least one data processing unit 101 in signal communication with the memory unit and configured to process data and store them in the memory unit.

[0035] According to a preferred embodiment, the method comprises a step for providing a graphical interface device 102 in signal communication with the memory unit and the data processing unit 101 and configured to display the data stored in the memory unit and / or processed by the data processing unit 101.

[0036] According to a preferred embodiment, the method includes the step of providing a machine 103 for delivering at least one or more drugs, the device being in signal communication with a memory unit, a data processing unit 101, and possibly a graphical interface device 102, and being configured to deliver drugs based on signals stored in the memory unit and / or processed by the data processing unit 101.

[0037] The method includes the following steps: providing the bispectral index (Pb) of an electroencephalogram (EEG) of a patient treated with a first anesthetic composition comprising an initial hypnotic concentration and an initial analgesic concentration. BIS ) and mean arterial pressure (P MAP ), and the patient's P BIS and P MAP The data is stored in the memory unit.

[0038] The bispectral index (BIS) is intended as a numerical parameter derived from a patient's electroencephalogram (EEG) to assess hypnotic levels under anesthesia. The BIS typically ranges from 0 to 100 and is correlated with clinical extremes of anesthesia. The BIS is a hypnotic parameter that measures the patient's brain state rather than the concentration of a specific drug.

[0039] The bispectral index of brainwaves is measured using techniques known to those skilled in the art (e.g., techniques described by Bruhn J. et al., “Depth of anaesthesia monitoring: what's available, what's validated and what's next?”, J. Bruhn, P.S. Myles, R. Sneyd, MMRFStruys, BJA: British Journal of Anaesthesia, Volume 97, Issue 1, July 2006, Pages 85–94, https: / / doi.org / 10.1093 / bja / ael120).

[0040] Mean arterial pressure (MAP) is defined as the average arterial pressure during the cardiac cycle and is associated with a patient's response to stress stimuli (such as surgery or procedures) under anesthesia. As is known to those skilled in the art, the MAP index is influenced by cardiac output and systemic vascular resistance, both of which are affected by several variables. MAP is commonly used in clinical practice to measure a patient's stress response and pressure due to insufficient tissue perfusion.

[0041] Blood pressure is the most common hemodynamic parameter recorded during anesthesia. Blood pressure can be measured by a monitoring system that detects data in an invasive way by positioning a dedicated catheter in the patient's artery, usually the radial artery, or in a non-invasive way by positioning a cuff connected to an appropriate monitoring system around the patient's arm. Anesthesia monitors use the oscillometric method for non-invasive blood pressure measurement. Techniques known to the person skilled in the art for MAP measurement are those described by Kai Kuck et al. in the document (Perioperative Noninvasive Blood Pressure Monitoring. Anaesth Analg 2018; 127:408-11) and by Karsten Bartels et al. in the document (Blood Pressure Monitoring for the Anaesthesiologist: A Practical Review. Anaesth Analg 2016; 122:1866-79).

[0042] To achieve the purposes of the method of the present application, MAP measurement is preferably carried out with a continuous non-invasive method for measuring the pressure at the level of the patient's finger.

[0043] The method comprises a step for preparing a two-dimensional matrix defined in the abscissa by a MAP dimension with respect to the variation of mean arterial pressure and in the ordinate by a BIS dimension with respect to the variation of the bispectral index.

[0044] Preferably, the step for arranging the two-dimensional matrix comprises a sub-step for arranging an algorithm which resides in the data processing unit 101 and is configured to define a two-dimensional matrix in the abscissa by a MAP dimension with respect to the variation of mean arterial pressure and in the ordinate by a BIS dimension with respect to the variation of the bispectral index.

[0045] The method comprises a step for defining, preferably using the algorithm, an optimal anesthesia zone (OAZ) located at MAP values between 65 and 110 mmHg and BIS values between 40 and 60.

[0046] It should be noted that the variation ranges of MAP and BIS dimensions in the optimal anesthesia zone (OAZ) are chosen to be related to important clinical purposes: the MAP value of 55 mmHg is the limit value for distinguishing moderate hypotension or severe hypotension; MAP values less than 55 mmHg are clinically associated with the development of postoperative renal failure and myocardial damage and a worse 30-day prognosis 7 .

[0047] The MAP value of 110 mmHg is the limit value for distinguishing between a moderate stress response and a severe stress response.

[0048] According to a preferred embodiment, the optimal anesthesia zone (OAZ) is located at a MAP value of 65 to 85 mmHg and a BIS value of 40 to 60.

[0049] Advantageously, the MAP variation range within the optimal anesthesia zone (OAZ), i.e. 65 mmHg to 85 mmHg, enables the patient to remain away from the limit values of 55 mmHg and 110 mmHg.

[0050] Without seeking to be bound by any theory, the Applicant believes that the MAP range of 65 mmHg to 85 mmHg can limit the variability of stress control during surgery.

[0051] As regards the BIS variation, prospective studies have shown that maintaining a BIS value of 40 to 60 during anesthesia ensures a sufficient hypnotic state 8 ; a BIS value of 30 enables to distinguish between a moderate depth of hypnosis or a severe depth of hypnosis.

[0052] Figure 3 A preferred embodiment of the matrix used in the method of the application is illustrated by way of example and not limitation.

[0053] According to a preferred embodiment, the matrix is defined by a MAP variation of 0 to 150 mmHg and a BIS variation of 0 to 100, wherein the MAP dimension and the BIS dimension intersect orthogonally to each other at the zero point (0; 0).

[0054] The method also comprises further steps for defining, preferably via an algorithm, in the matrix an ISO-MAP axis and an ISO-BIS axis orthogonal to the ISO-MAP, the intersection point of these axes defining the point (A) of the optimal anesthesia zone (OAZ).

[0055] According to a preferred embodiment, the point (A) is defined by the intersection of the ISO-MAP axis at a MAP value of 75 mmHg and the ISO-BIS axis at a BIS value of 50.

[0056] The method comprises steps for locating, via an algorithm, in the matrix the P BIS and P MAP data values, to define the position (B) of the patient in the matrix relative to the optimal anesthesia zone (OAZ).

[0057] The method comprises a step for providing an algorithm residing in said processing unit, the algorithm being configured to quantify a deviation of the patient position (B) from the optimal anesthesia zone (OAZ) and to transform the deviation into a quantitative change of the initial hypnotic concentration and / or of the initial analgesic concentration of the first anesthetic composition, to define a target hypnotic concentration and / or a target analgesic concentration of the second anesthetic composition.

[0058] According to a preferred embodiment, the algorithm configured to quantify a deviation of the patient position (B) from the optimal anesthesia zone (OAZ) and to transform the deviation into a quantitative change of the initial hypnotic concentration and / or of the initial analgesic concentration is further configured to define a two-dimensional matrix on the abscissa by means of a MAP dimension varying with respect to mean arterial pressure and on the ordinate by a BIS dimension varying with respect to bispectral index.

[0059] The method comprises a step for processing the P BIS and P MAP data of the patient by means of said algorithm to obtain a target hypnotic concentration and / or a target analgesic concentration of the second anesthetic composition.

[0060] It should be noted that the two ISO-BIS and ISO-MAP axes divide the matrix into four areas, each area corresponding to four main clinical situations that the algorithm must interpret: Figure 3 ): the upper right area (1) indicates an under anesthesia and it is characterized by an increase of the BIS value and of the MAP value; the lower left area (2) indicates a deep anesthesia and it is characterized by a decrease of the BIS value and of the MAP value. The lower right area (3) indicates an inadequate anesthesia in terms of both hypnotic and analgesic; this area is characterized by a decreasing BIS value and an increasing MAP value. The upper left area (4) indicates an under anesthesia condition and it is characterized by an increase of the BIS value and a decrease of the MAP value.

[0061] The areas (3) and (4) are the most problematic, since the BIS and MAP variations follow opposite trends and a different balance of hypnotic and analgesic concentrations must be identified to bring the patient back to the optimal anesthesia zone (OAZ).

[0062] It should be noted that the method of the present application is conditioned by the relative width of the BIS and MAP dimensions; in this sense, a greater percentage deviation can be attributed to a dimension characterized by a wider variation.

[0063] In order to make the BIS range and the MAP range equivalent, the method of the present application preferably comprises a further step for transforming the range of variation of the MAP dimension from the scale 0 to 150 (MAPscala150) to the scale 0 to 100 (MAPscala100).

[0064] Preferably, the MAP transformation on a scale from 0 to 100 (MAPscala100) is calculated with the following expression:

[0065] Equation 2 MAPscala100 = (MAPscala150 * 100) / 150

[0066] According to a preferred embodiment, the step of processing the data of the patient by means of an algorithm comprises the sub-step of: BIS and P MAP The step of processing the data of the patient by means of an algorithm comprises the sub-step of:

[0067] - quantifying the deviation of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) by means of vector calculation,

[0068] - decomposing the deviation of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) into a deviation of the hypnosis (H) with respect to the point (A) of the optimal anaesthesia zone (OAZ) and / or a deviation of the analgesia (S) with respect to the point (A), and

[0069] - calculating an increase or a decrease in the initial hypnotic and / or analgesic concentration of the first anaesthetic composition as a function of said deviations (D H ; D S ).

[0070] Preferably, the sub-step of quantifying the deviation of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) by means of vector calculation comprises the sub-step of defining a vector (V) passing through the point (A) of the optimal anaesthesia zone (OAZ) and passing through the patient position (B).

[0071] Figure 4 The algorithm illustrates the process of the sub-step of quantifying the deviation of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) by means of vector calculation.

[0072] Preferably, the sub-step of quantifying the deviation of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) by means of vector calculation comprises the sub-step of calculating the percentage deviation (D%) of the patient position (B) with respect to the point (A) of the optimal anaesthesia zone (OAZ) on the maximum deviation (C) of the MAP value and the BIS value along the vector (V).

[0073] More in detail, the percentage deviation (D%) is obtained with the following expression:

[0074] Equation 3

[0075] wherein,

[0076] - A-B corresponds to the distance between the patient position (B) and the point (A) of the optimal anaesthesia zone;

[0077] -A-C corresponds to the distance between the point (A) of the optimal anesthesia zone (OAZ) and the maximum deviation (C) of MAP and BIS along the vector (V).

[0078] According to a preferred embodiment, the distance (A-B) between the patient position (B) and the point (A) of the optimal anesthesia zone is calculated using the Pythagorean Theorem Figure 4 ).

[0079] Preferably, the distance (A-B) between the patient position (B) and the point (A) of the optimal anesthesia zone is obtained using the following expression:

[0080] Equation 4

[0081] wherein,

[0082] -A-E corresponds to the distance between the point (A) of the optimal anesthesia zone and the projection (E) of the patient position (B) on the ISO-BIS axis.

[0083] -B-E corresponds to the distance between the patient position (B) and the projection (E) of the patient position (B) on the ISO-BIS axis.

[0084] According to a preferred embodiment, the distance (A-C) between the point (A) of the optimal anesthesia zone (OAZ) and the maximum deviation (C) of MAP and BIS along the vector (V) is calculated using the Pythagorean Theorem.

[0085] Preferably, the distance (A-C) between the point (A) of the optimal anesthesia zone (OAZ) and the maximum deviation (C) of MAP and BIS along the vector (V) is obtained using the following expression:

[0086] Equation 5

[0087] wherein,

[0088] -A-D corresponds to the distance between the point (A) of the optimal anesthesia zone and the projection (D) of the maximum deviation (C) of MAP and BIS along the vector (V) on the ISO-BIS axis.

[0089] -C-D corresponds to the distance between the maximum deviation (C) of MAP and BIS along the vector (V) and the projection (D) of the maximum deviation (C) of MAP and BIS along the vector (V) on the ISO-BIS axis.

[0090] The maximum deviation (C) of the MAP value and the BIS value along the vector (V) corresponds to the intersection between the vector (V) passing through the point (A) and the patient position (B) and the outer edge of the matrix.

[0091] The definition of the vector (V) enables to characterize the parameter P BIS and P MAP the deviation with respect to the point (A) of the optimal anesthesia zone.

[0092] It should be noted that the matrix has an angular profile and, for this reason, the maximum deviation (C) of the MAP value and of the BIS value from the point (A) is not constant. The quantification of the deviation of the patient position (B) with respect to the optimal anesthesia zone (OAZ) in terms of percentage deviation (D%) advantageously enables to standardize the data, weighting the deviation of the patient position (B) with respect to the maximum deviation (C) of the MAP and of the BIS in each case.

[0093] Preferably, the sub-step for decomposing the deviation of the patient position (B) with respect to the optimal anesthesia zone (OAZ) comprises a sub-step for calculating the hypnotic deviation (D H ) by applying the percentage deviation (D%) of the patient position (B) with respect to the point (A) of the optimal anesthesia zone (OAZ) to the hypnotic coefficient (H’).

[0094] More in detail, the hypnotic deviation (D H ) is obtained by means of the following expression:

[0095] Equation 6 H D = H’ * D%

[0096] and the hypnotic coefficient (H’) is obtained by means of the following expression:

[0097] Equation 7

[0098] wherein,

[0099] - H’ is the hypnotic coefficient, obtained by dividing the hypnotic vector component (H) by the sum of the hypnotic vector component (H) and of the analgesic vector component (S);

[0100] - |H| is the absolute value of the hypnotic vector component, and corresponds to the distance (B-E) between the patient position (B) and the ISO-BIS axis;

[0101] - S is the analgesic vector component, and corresponds to the absolute value of the distance between the patient position (B) and the ISO-MAP axis. It is noted that the vector component S is equal in dimension to the distance A-E( Figure 4 ) between the point (A) of the optimal anesthesia zone and the projection (E) of the patient position (B) on the ISO-BIS axis.

[0102] More in detail, the hypnotic component H is obtained by means of the following expression:

[0103] Equation 8 H = P BIS - ISO-BIS

[0104] According to a preferred embodiment, when the ISO-BIS axis is defined by a BIS value of 50, the hypnotic vector component H is obtained with the following expression:

[0105] Equation 9 H = P BIS - 50

[0106] Similarly, the analgesic vector component S is obtained with the following expression:

[0107] Equation 10

[0108] wherein,

[0109] D(MAP) is the MAP dimension value of the projection (D) of the maximum deviation (C) of the MAP and BIS along the vector (V) on the ISO-BIS axis.

[0110] According to a preferred embodiment, when the ISO-MAP axis is defined by a MAP value of 75, the analgesic vector component S is obtained with the following expression:

[0111] Equation 11

[0112] According to a preferred embodiment, when the matrix is defined by a MAP variation between 0 and 150 mmHg, D(MAP) is 150 mmHg, and the analgesic vector component S is obtained with the following expression:

[0113] Equation 12

[0114] Similarly, the sub-step for decomposing the deviation of the patient position (B) with respect to the point (A) of the optimal anesthesia zone (OAZ) comprises a sub-step for calculating the analgesic deviation (D S ) by applying the percentage deviation (D%) of the patient position (B) with respect to the point (A) of the optimal anesthesia zone (OAZ) to the analgesic coefficient (S’).

[0115] More in detail, the analgesic deviation (D S ) is obtained by the following expression:

[0116] Equation 13 D S = S’ * D%

[0117] and the analgesic coefficient (S’) is obtained with the following expression:

[0118] Equation 14

[0119] wherein the analgesic coefficient (S') is obtained by dividing the analgesic vector component (S) by the sum of the analgesic vector component (S) and the hypnotic vector component (H), in absolute value form.

[0120] It should be noted that the distance from the ISO-BIS axis makes it possible to determine the degree of deviation from the hypnotic state of the patient, while the distance from the ISO-MAP makes it possible to determine the degree of deviation from the analgesic state of the patient, i.e. from the stress-free state.

[0121] Preferably, the hypnotic deviation (D H ) and the analgesic deviation (D S ) are used in the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration of the first anesthetic composition.

[0122] According to a preferred embodiment, the method comprises a step for providing a minimum hypnotic and analgesic concentration ([c min ]) and storing this minimum concentration in a memory unit.

[0123] It should be noted that the minimum concentration is intended as the minimum concentration that can be administered to the patient to produce the desired anesthetic effect.

[0124] Figure 5 The algorithm illustrates the process of the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration.

[0125] According to an alternative embodiment, the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration comprises the following sub-steps:

[0126] - if the percentage deviation (D%) of the patient position (B) from the point (A) of the optimal anesthetic zone (OAZ) is greater than 10%, the hypnotic and / or analgesic concentration is modified.

[0127] Advantageously, the algorithm provides that within this limit value of the percentage deviation (D%), since the deviation from the optimal anesthetic zone (OAZ) is negligible, there is no need to intervene on the hypnotic and / or analgesic concentration to be administered to the patient.

[0128] According to a preferred embodiment, the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration comprises the following sub-steps:

[0129] - if the hypnotic deviation (D H ) is greater than 7.5%, the hypnotic concentration is modified; and

[0130] - if the analgesic deviation (D S ) is greater than 7.5%, the analgesic concentration is modified.

[0131] Advantageously, the algorithm provides that, within the limits of the hypnotic deviation (D H ) and of the analgesic deviation (D S ), since the variables under analysis (D H ; D S ) are within an acceptable range outside the optimal anesthesia zone (OAZ), there is no need to intervene on the hypnotic and / or analgesic concentration to be administered to the patient.

[0132] Preferably, the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration makes it possible to transform the hypnotic deviation (D H ) and / or the analgesic deviation (D S ) into a variation delta of the initial hypnotic and / or analgesic concentration.

[0133] Preferably, the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration comprises the following sub-steps:

[0134] - if the percentage deviation (D%) of the patient position (B) from the point (A) of the optimal anesthesia zone (OAZ) is greater than 10% and at the same time the hypnotic deviation (D H ) is greater than 7.5%, the hypnotic concentration is modified;

[0135] - if the percentage deviation (D%) of the patient position (B) from the point (A) of the optimal anesthesia zone (OAZ) is greater than 10% and at the same time the analgesic deviation (D S ) is greater than 7.5%, the analgesic concentration is modified.

[0136] It should be noted that, preferably, during the sub-step for calculating the increase or decrease of the initial hypnotic and / or analgesic concentration, the algorithm successively judges:

[0137] 1) whether the percentage deviation (D%) of the patient position (B) from the point (A) of the optimal anesthesia zone (OAZ) is greater than or less than 10%;

[0138] 2) when the percentage deviation (D%) is greater than 10%, the algorithm judges whether the hypnotic deviation (D H ) or the analgesic deviation (D S ) is greater than or less than 7.5%;

[0139] 3) when the hypnotic deviation (D H ) or the analgesic deviation (D S ) is greater than 7.5%, the algorithm calculates the increase or decrease of the initial hypnotic and / or analgesic concentration.

[0140] Preferably, the sub-step for calculating the concentration increase comprises the following sub-steps:

[0141] - the hypnotic deviation (D H ) or the analgesic deviation (D S ) is applied to the difference between the maximum hypnotic and / or analgesic concentration ([c max ]) and the initial hypnotic and / or analgesic concentration ([c in ]), which is added to the initial hypnotic and / or analgesic concentration ([c in ]) to obtain the increased difference of the initial hypnotic and / or analgesic concentration.

[0142] In more detail, the concentration increase is calculated using the following expression:

[0143] Equation 15 [c target ] ↑ = [c in ]+ {D H / S* ([c max ]- [c in ])}

[0144] It should be noted that the maximum hypnotic and / or analgesic concentration is intended as the maximum concentration that can be administered to the patient which will produce the desired effect without unacceptable side effects.

[0145] For Remifentanil and Propofol, a simplified formula for calculating the concentration increase can be determined; in these cases, the sub-step for calculating the concentration increase preferably comprises the following sub-steps:

[0146] - the hypnotic deviation (D H ) or the analgesic deviation (D S ) is applied to the empirical constant (k), which is added to the initial hypnotic and / or analgesic concentration ([c in ]) to obtain the increased difference of the initial hypnotic and / or analgesic concentration,

[0147] where the empirical constant (k):

[0148] for Propofol is 3 μg / mL; and

[0149] for Remifentanil is 6 μg / mL.

[0150] In more detail, the concentration increase of Propofol and Remifentanil is calculated using the following expression:

[0151] Equation 15a [c target ] ↑ = [c in ]+ {DH / S* k 丙泊酚 / 瑞芬太尼}

[0152] According to a preferred embodiment, when the hypnotic is propofol, the concentration increase is calculated using the following expression:

[0153] Equation 16 [c target ] ↑丙泊酚 = [c in ] 丙泊酚 + (D H * 3)

[0154] According to a preferred embodiment, when the sedative is remifentanil, the concentration increase is calculated using the following expression:

[0155] Equation 17 [c target ] ↑瑞芬太尼 = [c in ] 瑞芬太尼 + (D S * 6)

[0156] Preferably, the sub-step for calculating the concentration decrease comprises the following sub-steps:

[0157] applying the hypnotic deviation (D H ) or the analgesic deviation (D S ) to the initial hypnotic and / or analgesic concentration ([c in ]) subtracting it from the initial hypnotic and / or analgesic concentration ([c in ]) to obtain a reduced amount of the initial hypnotic and / or analgesic deviation.

[0158] More in detail, the concentration decrease is calculated using the following expression:

[0159] Equation 18 [c target ] ↓ = [c in ] - (D H / S* [c in ])

[0160] According to a preferred embodiment, when the hypnotic is propofol, the concentration decrease is calculated using the following expression:

[0161] Equation 19 [c target ] ↓丙泊酚 = [c in ] 丙泊酚 - ([c in ] 丙泊酚 * [D H ])

[0162] According to a preferred embodiment, when the sedative is remifentanil, the concentration is calculated using the following expression decrease :

[0163] Equation 20 [c target ] ↓瑞芬太尼 = [c in ] 瑞芬太尼 - ([c in ] 瑞芬太尼 * [D S ])

[0164] Note that equations 18, 19 and 20 for calculating a decrease in concentration can intervene more aggressively in the level of anesthesia than equations 15, 15a, 16 and 17 for calculating an increase in concentration. This different mathematical approach is justified mainly by the fact that a hypotensive state, usually associated with low BIS values, requires a rapid intervention to prevent serious organ damage to the heart, brain and kidneys. The limitation of this equation is that the algorithm is able to reset the concentration of anesthetic, and this intervention is not always justified. Therefore, in the clinical implementation of the invention, it will be necessary to provide lower concentration limits for each anesthetic using a function that limits the intervention of the algorithm. The concentration limits cannot be derived from the vector analysis. The lower concentration limit can vary depending on the timing of the procedure, the administration of muscle relaxants or the administration of drugs that contribute to the anesthetic state, such as morphine, etc. The lower concentration limit for each step of the surgical procedure should be set based on data from the literature and the principles of good clinical practice.

[0165] According to a preferred embodiment, when the initial hypnotic or analgesic concentration is modified during the sub-step for calculating an increase or decrease in the initial hypnotic or analgesic concentration, the method comprises the following steps:

[0166] - generating, by means of the algorithm, a datum related to the target hypnotic and analgesic concentration of the second anesthetic composition, the datum being configured to cause the processing unit to generate:

[0167] - a signal receivable by the graphic interface device 102, the graphic interface device 102 being configured to display the target hypnotic and sedative concentration processed by the algorithm ( Figure 8 ), and / or

[0168] - a signal receivable by the machine 103, the machine 103 being configured for delivering one or more drugs ( Figure 7 ).

[0169] Preferably, the datum related to the target hypnotic and analgesic concentration of the second anesthetic composition is recorded in the memory unit by the processing unit.

[0170] Preferably, when the algorithm generates the benchmark related to the target hypnotic and analgesic concentrations of the second anesthetic composition, the method comprises the following steps:

[0171] - generating, by means of the processing unit, a signal from the benchmark related to the target hypnotic and analgesic concentrations and sending this signal to the graphic interface device 102 configured to display the target hypnotic and sedative concentrations processed by the algorithm; and / or

[0172] - generating a signal from the benchmark related to the target hypnotic and analgesic concentrations and sending this signal to the machine 103 configured to deliver one or more drugs according to the target hypnotic and sedative concentrations processed by the algorithm.

[0173] Preferably, the method of the application comprises further steps for the anesthetist to approve, by means of the graphic interface, the benchmark related to the target hypnotic and analgesic concentrations of the second anesthetic composition.

[0174] In particular, when the benchmark is displayed on the graphic interface, the approval step preferably comprises the following sub-steps:

[0175] - confirming the sending of the signal related to the benchmark of the target hypnotic and analgesic concentrations of the second anesthetic composition to the delivery machine 103.

[0176] In particular, when the benchmark is sent to the delivery machine 103, or when it is sent to the delivery machine 103 and to the graphic interface device 102 simultaneously, the approval step preferably comprises the following sub-steps:

[0177] - starting, by means of the delivery machine 103, the delivery of the drugs according to the benchmark of the target hypnotic and analgesic concentrations of the second anesthetic composition.

[0178] Another object of the application is a system for carrying out the method of the application. The system comprises:

[0179] - a memory unit configured to receive and store data;

[0180] - a data processing unit 101 in signal communication with the memory unit and configured to process data and store it in the memory unit;

[0181] - an algorithm residing in the data processing unit 101 and configured to:

[0182] - define a two-dimensional matrix on the abscissa by means of a MAP dimension varying with respect to mean arterial pressure and on the ordinate by a BIS dimension varying with respect to the bispectral index;

[0183] - defining in the matrix an optimal anesthesia zone (OAZ) of MAP values comprised between 65 and 110 mmHg and BIS values comprised between 40 and 60;

[0184] - defining in the matrix an ISO-MAP axis and an ISO-BIS axis orthogonal to the ISO-MAP axis, the intersection of the ISO-MAP axis and the ISO-BIS axis defining a point (A) of the optimal anesthesia zone (OAZ);

[0185] - positioning P BIS and P MAP - the values of the data to define in the matrix the position (B) of the patient with respect to the optimal anesthesia zone (OAZ);

[0186] - an algorithm, which resides in the processing unit 101, which is configured to quantify the deviation of the patient position (B) with respect to the optimal anesthesia zone (OAZ) and to transform this deviation into a quantitative variation of the initial hypnotic concentration and of the initial analgesic concentration of the first anesthetic composition, to define the target hypnotic concentration and the target analgesic concentration of the second anesthetic composition.

[0187] Preferably, the memory unit is provided with a plurality of memory areas in which the data received by the data processing unit are stored.

[0188] More preferably, the processing unit is configured to:

[0189] - perform an algorithm, which resides in said processing unit, which is configured to quantify the deviation of the patient position (B) with respect to the optimal anesthesia zone (OAZ) and to transform this deviation into a quantitative variation of the initial hypnotic concentration and of the initial analgesic concentration of the first anesthetic composition, to define the target hypnotic concentration and the target analgesic concentration of the second anesthetic composition; and

[0190] - process the P BIS and P MAP data of the patient by means of said algorithm to obtain the target hypnotic concentration and / or the target anesthetic concentration of the second anesthetic composition.

[0191] Preferably, the processing unit is configured to perform an algorithm which resides in the processing unit 101 and which is configured to define a two-dimensional matrix on the abscissa by means of a MAP dimension which varies with respect to the mean arterial pressure and on the ordinate by means of a BIS dimension which varies with respect to the bispectral index.

[0192] According to a preferred embodiment, the system comprises:

[0193] - a graphic interface device 102 in signal communication with the memory unit and with the data processing unit 101 and configured to display data stored in the memory unit and / or processed by the data processing unit 101, and / or

[0194] - a machine 103 for delivering one or more drugs, in signal communication with the memory unit, with the data processing unit, possibly with the graphic interface device 102, and configured to deliver drugs according to signals stored in the memory unit and / or processed by the data processing unit 101.

[0195] Preferably, the graphic interface device 102 is configured to receive reference values relating to target hypnotic and analgesic concentrations of the second anesthetic composition; preferably, the received reference values are displayed on the device in graphic interface by means of a computer program configured for this display purpose.

[0196] The graphic interface device can be configured to receive and display in the same graphic interface the P BIS and P MAP data processed by means of an algorithm resident in the data processing unit 101; by way of example and not limitation, such additional data can be:

[0197] - the P BIS and P MAP data recorded in the memory unit by the patient monitoring unit 100; and / or

[0198] - data relating to the percentage deviation value (D%) of the patient position (B) from the point (A), to the hypnotic deviation (D H ) and to the analgesic deviation (D S ), and / or

[0199] - a two-dimensional matrix and an optimal anesthetic zone (OAZ).

[0200] Preferably, the drug delivery machine 103 is configured to deliver at least one hypnotic and one analgesic.

[0201] Preferably, the machine 103 is configured to receive reference values relating to target hypnotic and analgesic concentrations of the second anesthetic composition and to deliver target hypnotic and analgesic concentrations of the second anesthetic composition processed by means of an algorithm by the data processing unit 101 on the basis of the reference values and preferably with the approval of the anesthetist.

[0202] According to a preferred embodiment, the machine 103 is also configured to detect the blood concentration of the one or more drugs administered to the patient and to generate a reference relating to this information. Preferably, said blood concentration of the one or more drugs administered to the patient is the initial hypnotic and analgesic concentration of the first anesthetic composition. The machine is preferably configured to generate in the memory unit a reference relating to the blood concentration of the one or more drugs administered to the patient, the reference being configured to cause the data processing unit 101 to record data from the memory unit and / or to cause the data processing unit 101 to generate a signal receivable by the graphic interface device 102, the graphic interface device 102 being configured to display the hypnotic and sedative blood concentration.

[0203] Preferably, the data processing unit 101 is configured to read the reference relating to the initial hypnotic and analgesic concentration of the first anesthetic composition when it is recorded in the memory unit and to integrate it in the processing of the target hypnotic and analgesic concentration of the second anesthetic composition by means of the algorithm.

[0204] According to a preferred embodiment, the system also comprises a patient monitoring unit 100 provided with sensors configured to measure the patient's cerebral electrical double frequency index (P BIS ) and mean arterial pressure (P MAP ). The monitoring unit 100 is preferably in signal communication with the memory unit, with the data processing unit, possibly with the graphic interface device 102, possibly with the machine 103 configured to deliver one or more drugs.

[0205] The patient monitoring unit 100 is preferably configured to generate a reference relating to the patient's cerebral electrical double frequency index (P BIS ) and mean arterial pressure (P MAP ), the data being configured to cause the data processing unit 101 to record it in the memory unit.

[0206] Preferably, the data processing unit 101 is configured to read the reference relating to the cerebral electrical double frequency index (P BIS ) and mean arterial pressure (P MAP ) when it is recorded in the memory unit and to integrate it in the processing of the target hypnotic and analgesic concentration of the second anesthetic composition by means of the algorithm resident in the data processing unit 101.

[0207] Figure 7schematically represents a preferred embodiment of the method of the present application, in which the step for approving the reference relating to the target hypnotic and analgesic (sedative) concentration is considered; this diagram enables the technical action encompassed by the algorithm in the process of controlling the concentration of the anesthetic composition to be understood. In this case, the method is implemented in a system comprising:

[0208] - a patient monitoring unit 100, provided with sensors configured for measuring the patient's bispectral index (BIS) and mean arterial pressure (MAP); BIS ) and mean arterial pressure (MAP); MAP

[0209] - a data processing unit 101, in signal communication with the monitoring unit 100, configured to process the data from the monitoring unit 100 by means of an algorithm resident in the data processing unit 101, configured for predisposition and determination of both the target hypnotic and analgesic concentration in a two-dimensional matrix;

[0210] - a memory unit (not visible in the diagram), in signal communication with the data processing unit 101 and the patient monitoring unit 100, configured to receive and record the data from the units;

[0211] - a graphic interface device 102, on which the data relating to the target hypnotic and analgesic concentration processed by the data processing unit 101 and the patient monitoring data recorded in the memory unit by the monitoring unit 100 can be displayed by means of the algorithm; the graphic interface device 102 is a device that enables the anesthesiologist to view the system output, thus confirming the sending of the signal relating to the reference of the target hypnotic and analgesic concentration of the second anesthetic composition to the delivery machine 103;

[0212] - a machine 103, configured for delivering one or more drugs by means of intravenous infusion; the machine 103 is configured to send and receive data with respect to the memory unit and the data processing unit 101; in the specific embodiment shown, the machine 103 is configured to monitor the blood concentration of the hypnotic and analgesic drugs infused into the patient and to generate a reference relating to such concentration, for example to cause the data processing unit 101 to record this data in the memory unit. The data processing unit 101 integrates the reference relating to the (initial) hypnotic and analgesic blood concentration into the process of increasing or decreasing the hypnotic and analgesic concentration by means of the algorithm. Figure 8

[0213] ​​A system suitable for this purpose is, for example, an infusion system (TCI: Target Controlled Infusion) which converts a certain target concentration set by the anesthesiologist into a corresponding amount of drug to be delivered by a pump / syringe in time units to reach the preset target. The conversion is automatically performed by a microprocessor contained in the infusion system, which is programmed with an algorithm comprising a pharmacokinetic model of the drug used.

[0214] With reference to Figure 7 The depicted embodiment, it should be noted that the processing unit 101 provides, by means of an algorithm, a two-dimensional matrix defined by the MAP dimension (0 to 150 mmHg) and the BIS dimension (0 to 100); the processing unit detects the P BIS and P MAP values of the patient recorded in the memory unit by the monitoring unit 100 and processes these data by means of an algorithm with a vector analysis (example 2) 101a (the vector analysis serves to quantify the percentage deviation (D%) of the patient position (B) from the optimal anesthetic zone (OAZ)); if the algorithm judges that the percentage deviation (D%) is greater than 10%, the algorithm proceeds to the analysis 101b of the hypnotic (D H ) and analgesic (D S ) vector components; if the algorithm judges that at least one of the hypnotic (D H ) and analgesic (D S ) vector components is greater than 7.5%, the algorithm proceeds to the calculation 101c of the increase or decrease to be applied to the initial hypnotic and analgesic concentration. The algorithm then generates a reference related to the increase or decrease of the initial hypnotic and analgesic concentration and causes the processing unit to generate a signal configured to be displayed on the graphic interface device 102. The anesthesiologist, viewing the data on the graphic interface, proceeds or does not proceed to the approval step, thus confirming, where deemed appropriate, the sending of the signal related to the reference of the target hypnotic and analgesic concentration of the second anesthetic composition to the delivery machine 103.

[0215] Figure 8 The figure shows an example of how the reference related to the increase or decrease of the initial hypnotic and analgesic concentration can be displayed on the graphic interface of the computer program configured to implement the method of the present application. The graphic interface displays the P BIS and P MAP values (current values) and the target P BIS and P MAP values (target) intended to be achieved for the induction, maintenance and termination (awakening) of controlled anesthesia. In Figure 8In an embodiment of the graphical interface, the values of the segments A-E, A-D, B-E, C-D defined on the two-dimensional matrix are displayed for determining the distance A-B of the patient position (B) from the optimal anesthetic zone (OAZ) by means of the Pythagorean theorem. The graphical interface displays the output of the calculations derived from the vector analysis and, in particular, the hypnotic (H') and analgesic (D') coefficients, the percentage deviation (D%) and the hypnotic (D H ) and analgesic (D S ) vector components. Finally, the graphical interface displays the reference associated with the increase or decrease of the initial hypnotic and analgesic concentrations, thus providing the anesthetist with a reference associated with the target hypnotic and analgesic concentrations for bringing the patient back to the optimal anesthetic zone (OAZ) defined by the two-dimensional matrix.

[0216] According to a preferred embodiment, the graphical interface is also able to cause the two-dimensional matrix and the patient position (B) with respect to the optimal anesthetic zone (OAZ) to be monitored visually for the variations.

[0217] Another object of the present application is a computer program configured to perform the method of the present application when executed by a computer.

[0218] It should be noted that the computer program can use general data management functions to perform the steps of the method of the present application.

[0219] The person skilled in the art understands that all or some of the steps for implementing the method can be performed by hardware associated with the program instructions; the program can be stored in a computer readable storage medium or in a computer, such as one or more computer readable instructions.

[0220] As mentioned herein, a "storage medium" can mean a medium capable of storing information or instructions activatable or executable by one or more processors. For example, the storage medium can include a database for storing instructions or information readable by a microprocessor.

[0221] If the computer readable program instructions are executed, they can enable the computing platform to perform one or more actions. According to a preferred embodiment, the computing platform is the software of the drug delivery machine 103.

[0222] According to a preferred embodiment, the computer on which the program is executed is in signal communication with a memory unit configured to receive and record the data; according to an alternative embodiment, the computer on which the program is executed is in signal communication with sensors configured for measuring the cerebral electrical bi-frequency index (P BIS ) and the mean arterial pressure (P MAP ) of the patient.

[0223] Another subject of the present application is a Proportional-Integral-Derivative (PID) controller configured to implement the method of the present application.

[0224] The method of the present application can be implemented by using a conventional PID controller configured to maintain or adjust the processed parameter to a predetermined value as a function of its deviation from a predetermined range by means of correction means known to the person skilled in the art.

[0225] According to one example application, the PID controller can be integrated into a system for controlling the concentration of hypnotics and / or analgesics during anesthesia and configured to be in signal communication with:

[0226] - a memory unit configured to receive and record data;

[0227] - at least one sensor for measuring the concentration of hypnotics and / or analgesics in the blood of the patient, in signal communication with the memory unit;

[0228] - a drug delivery unit configured to deliver at least one hypnotic and one analgesic.

[0229] The PID controller thus integrated can be configured to implement the method of the present application and to generate at least one signal based on the difference between the target concentration of hypnotics and / or analgesics obtained by implementing the method of the present application and the concentration of hypnotics and / or analgesics measured in the blood of the patient, which, if applied to the delivery unit, will cause the release of hypnotics and / or analgesics to stabilize the concentration of hypnotics and / or analgesics in the blood of the patient to the target concentration.

[0230] The PID control system can be configured to implement the method of the present application, for example, in a total intravenous delivery system.

[0231] The method of the present application can provide significant support to the anesthetist to help him define a strategy for adjusting and controlling the concentration of anesthetics during anesthesia; it should be noted that in any case, by virtue of the clinical experience acquired in the sector, the choice of the drug for the target concentration of hypnotics and / or anesthetics obtained by processing the P BIS and P MAP data, the choice to deviate partially or totally from the strategy proposed by the method of the present application, is still the responsibility of the physician.

[0232] Example

[0233] By way of example and not limitation, below an exemplary embodiment of the method of the present application is given.

[0234] Example 1

[0235] 1. Algorithm response test

[0236] The following tests show how the calculation based on the method of the present application is carried out in clinical practice for controlling hypnotic and analgesic concentrations.

[0237] For this purpose, a number of previously recorded non-simulated clinical anaesthesia situations were analysed retrospectively.

[0238] For each anaesthesia process analysed, the maintenance step (i.e. the time period between the skin incision and the beginning of the surgical suture) was considered.

[0239] The data were extracted from the anaesthesia records as individual monitoring points, which were characterized by the combination of P BIS and P MAP values together with the respective concentrations of the two anaesthetics (propofol (hypnotic) and remifentanil (opioid analgesic)). The concentrations shown are to be understood as the concentrations expected at the site of action.

[0240] For the purposes of the test, the matrix was defined as follows:

[0241] - MAP dimension: from 0 to 150 mmHg;

[0242] - BIS dimension: from 0 to 100;

[0243] - OAZ: MAP values from 65 to 85 mmHg and BIS values from 40 to 60;

[0244] - Point (A) in the OAZ: MAP equal to 75 mmHg and BIS equal to 50.

[0245] Table 1 collects 3 monitoring points, which are characterized by a percentage deviation (D%) from 1% to 8%.

[0246] These three points (e.g. 1 to 3) fall within the optimal anaesthesia zone (OAZ) and are within the permitted variation limits in terms of percentage deviation (D%) as well as hypnotic deviation (D H ) and analgesic deviation (D S ). When applied to such monitoring points, the algorithm does not perform either hypnotic concentration correction or opioid concentration correction.

[0247] 1.1 Zone (1) - increased BIS and MAP

[0248] Zone (1) corresponds to conditions of light anaesthesia both in terms of hypnotics and in terms of analgesics. In this zone, the algorithm based on the method of the present application intervenes to correct both the analgesic components to bring the patient to the optimal anaesthesia conditions.

[0249] Table 2 collects the 3 monitoring points located in the area (1) of the matrix for the test; when applied to these monitoring points, the algorithm intervenes on the calculation of both hypnotic and opioid concentrations, determining, if necessary, an increasing increment of the individual anesthetic.

[0250] In the case of the monitoring points numbered 2 and 3, they are characterized by a P BIS The smaller difference in values is characterized by a percentage deviation (D%) of 29.3% and 26.0% respectively recorded.

[0251] Although minimal, this difference leads to a different orientation of the vector (V) describing the distance of the individual monitoring point (patient position (B)) from the center (A) of the optimal anesthetic zone (OAZ). In an angular system such as that of the matrix used in the method, the smaller difference in the orientation of the vector changes the distance of the patient position (B) from the point (A) of the optimal anesthetic zone (OAZ) and, therefore, the percentage contribution of the individual vector to the maximum distance (C) from the center.

[0252] 1.2 Area (2) - reduced BIS and MAP

[0253] Area (2) corresponds to the case of deep anesthesia both in terms of hypnotic component and in terms of analgesic component. In this area, the algorithm based on the method of the present application proposes to lighten both these anesthetic components to bring the patient to the optimal anesthetic condition.

[0254] Table 3 includes 3 monitoring points within area (2) for test purposes. Only one monitoring point is the one on which the algorithm operates with simultaneous calculation of both anesthetic components to reduce both propofol and remifentanil concentrations.

[0255] For the remaining 2 monitoring points, the algorithm intervenes only on the calculation of one of the two drugs: in both cases the concentration of propofol is reduced.

[0256] 1.3 Area (3) - reduced BIS and increased MAP

[0257] Area (3) corresponds to the case of deep anesthesia in terms of hypnotic component and of insufficient analgesic component to control the stress response to trauma.

[0258] Table 4 collects 3 monitoring points located in area (3) of the matrix for test purposes.

[0259] For point 1, the control variable that activates the execution of the algorithm is P BIS and, in this sense, the calculation intervention on propofol concentration is recorded.

[0260] For point n. 2, the interventions on both anesthetics are recorded: decrease of propofol concentration and increase of remifentanil concentration. In three other cases, the control variable outside the optimal range is P MAP and the recorded interventions concern only the concentration of remifentanil.

[0261] 1.4 Zone (4) - increased BIS and decreased MAP

[0262] Zone (4) corresponds to anesthetic situations in which the hypnotic component is insufficient and the MAP value is lower than the optimal anesthetic zone.

[0263] Table 5 includes 3 monitoring points located in zone (4) for test purposes. The behavior of the method of the present application, and in particular the algorithm implemented therein, is evident from the P BIS and P MAP values outside the limits allowed by the system; in this case, the interventions on the concentrations of both hypnotics are recorded (increase of propofol and decrease of remifentanil).

[0264] In the other two points, the algorithm stops and does not intervene on the calculation of the propofol concentration since the hypnotic deviation (D H ) is less than 7.5%.

[0265] 2. CONCLUSIONS

[0266] The test has made it possible to show how the calculation based on the method of the present application can be used to define a strategy for adjusting the concentrations of anesthetics in a scenario with non-simulated data. The calculation interventions of the system are always in agreement with the clinical situations recorded in the documentation.

[0267]

[0268] Table 1

[0269]

[0270] Table 2

[0271]

[0272] Table 3

[0273]

[0274] Table 4

[0275]

[0276] Table 5

[0277] Note that the values of D, D H and D S reported in Tables 1 to 5 are expressed in absolute values.

[0278] Example 2

[0279] 1. Baseline clinical situation:

[0280] P BIS = 75, P MAP = 130 mmHg

[0281] Propofol [Ce]: 3.0 mcg / mL

[0282] Remifentanil [Ce]: 5.0 ng / mL

[0283] 2. Calculation of the percentage deviation (D%)

[0284] The two-dimensional matrix is described as a Cartesian plane defined on the abscissa by MAP (from 0 to 150 mmHg) and on the ordinate by BIS (from 0 to 100), where the dimensions MAP and BIS intersect orthogonally to each other at the point zero (0; 0).

[0285] The matrix is further defined by the ISO-MAP axis at the MAP value of 75 mmHg and the ISO-BIS axis at the BIS value of 50; the center of the Cartesian plane corresponds to BIS = 50 and MAP = 75 mmHg. The center of the Cartesian plane corresponds to the point (A) of the optimal anesthesia zone (OAZ).

[0286] The distance between points on the plane is calculated using the Pythagorean theorem.

[0287] In the example ( Figure 6 ), segment A-B identifies the hypotenuse, A-E and B-E identify two sides of the same triangle (catheter). Similarly, A-C coordinates identify the hypotenuse, A-D and C-D identify two sides of the corresponding triangle.

[0288] The value of point B on the abscissa corresponds to P MAP ; the value of point B on the ordinate corresponds to P BIS .

[0289] Therefore, the algorithm uses:

[0290] Equation 4: (AB: V(AE 2 + BE 2 ), to determine the distance between points A and B;

[0291] Equation 5: (AC: V(AD 2 + CD 2 ), to determine the distance between points A and C.

[0292]

[0293] 3. Calculation of the hypnotic (H) and analgesic (S) vector components

[0294] This algorithm analyzes the distance of the head (A) of the vector (A-B) from the orthogonal axis defined by the coordinates BIS 50 (ISO-BIS axis) and from the orthogonal axis defined by the MAP 75 mmHg (ISO-MAP axis).

[0295] The distance of the head (A) of the vector AB from the ISO-BIS axis is shown as component "H" and is calculated according to equation 9:

[0296] (H = P BIS - 50) / 150) * 100.

[0297] The distance of the head (A) of the vector AB from the ISO-MAP axis is shown as component "S" and is calculated according to equation 12:

[0298] (S = [(P MAP - 75) / 150] * 100.

[0299] This calculation method meets the need to prevent the greater width of the MAP dimension in the vector calculation from causing a greater weight of this variable.

[0300] These two vector components "H" and "S" are used to quantify the fraction of D% attributable to the hypnotic component (called D H ) and the fraction of D% attributable to the analgesic component (called D S ) according to the following expressions:

[0301] Equation 7: D H = [H / (|H| + |S|)] * D%

[0302] Equation 14: D S = [S / (|H| + |S|)] * D%

[0303] D H and D S are the percentages that quantify the interventions to be performed on hypnotics and analgesics for each time the patient leaves the OAZ.

[0304]

[0305] 4. Numerical calculation of the titration

[0306] This step of the algorithm will output the vector analysis (D H and D S) with concentration data from a controlled infusion system (TCI) to define useful target concentrations of propofol and remifentanil that put the patient into the OAZ. This system is designed to intervene on the concentration of anesthetic drugs and cannot directly manage the dose or infusion rate. Drug concentration should be understood as the effect site concentration (Ce) provided by the controlled infusion system (TCI).

[0307] If the therapeutic goal is an increase or decrease in drug concentration, the equation used to quantify the intervention on the anesthetic is different.

[0308] In this example embodiment, the drugs used are remifentanil and propofol; the following is the equation to calculate the increase in its concentration:

[0309] Equation 16: [c target ] ↑丙泊酚 = [c in ] 丙泊酚 + (D H * 3)

[0310] Equation 17: [c target ] ↑瑞芬太尼 = [c in ] 瑞芬太尼 + (D S * 6)

[0311] The equation to calculate the decrease in its concentration is shown below:

[0312] Equation 19: [c target ] ↓丙泊酚 = [c in ] 丙泊酚 + ([c in ] 丙泊酚 * [-D H ])

[0313] Equation 20: [c target ] ↓瑞芬太尼 = [c in ] 瑞芬太尼 ([c in ] 瑞芬太尼 * [-D S ])

[0314]

[0315] REFERENCES

[0316] 1. Lundy JS. Balanced anaesthesia. Minn Med 1926; 9: 399.

[0317] 2. P. H. Tonner. Balanced anaesthesia today. Best Practice & Research Clinical Anaesthesiology 2005, 19(3):475-484.

[0318] 3. William R Greco et al. The Search for Synergy: A Critical review from a Response Surface Prospective. PHARMACOLOGICAL REVIEWS 1995, 47(2):331-385.

[0319] 4. Jaap Vuyk et al. Propofol Anaesthesia and Rational Opioid Selection: Determination of Optimal EC50-EC95 Propofol-Opioid Concentrations that Assure Adequate Anaesthesia and a Rapid Return of Consciousness. Anaesthesiology 1997, 87(12): 1549-1562.

[0320] 5. an F. A. Hendrickx et al. Is Synergy the Rule? A Review of Anaesthetic Interactions Producing Hypnosis and Immobility. Anaesthesia & Analgesia: August 2008-Volume 107-Issue 2-p 494-506.

[0321] 6. Gurman GM. Assessment of depth of general anaesthesia. Observations on processed EEG and spectral edge frequency. Int J Clin Monit Comput 1994; 11: 185-9.

[0322] 7. Daniel I. Sessler et al. Hospital Stay and Mortality Are Increased in Patients Having a "Triple Low" of Low Blood Pressure, Low Bispectral Index, and Low Minimum Alveolar Concentration of Volatile Anaesthesia. Anaesthesiology 2012; 116: 1195-203.

[0323] 8. Gan TJ, Glass PS, Windsor A, Payne F, Rosow C, Sebel P, Manberg P. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anaesthesia. BIS Utility Study Group. Anaesthesiology 1997; 87: 808-15.

Claims

1. A method for controlling the concentration of a hypnotic and analgesic in an anesthetic composition, the method comprising the following steps: - Provide a memory unit configured to receive and record data; - Provide at least one data processing unit (101), which communicates with the memory unit via signals and is configured to process data and record the data in the memory unit; - Provides the bispectral index (Pb) of the electroencephalogram (EEG) of patients treated with a first anesthetic composition comprising an initial hypnotic concentration and an initial analgesic concentration. BIS ) and mean arterial pressure (P MAP ), and the patient's P BIS and P MAP Data is stored in the memory unit. The method is characterized by further including the following steps: - Provide a two-dimensional matrix, which is defined on the horizontal axis by the MAP dimension relative to the change in mean arterial pressure and on the vertical axis by the BIS dimension relative to the change in the bispectral index of the electroencephalogram; - Define the optimal anesthesia zone (OAZ) in the matrix, with MAP values ​​between 65 and 110 mmHg and BIS values ​​between 40 and 60. - Define the ISO-MAP axis and the ISO-BIS axis orthogonal to the ISO-MAP axis in the matrix, and define the point (A) of the optimal anesthesia zone (OAZ) at the intersection of the ISO-MAP axis and the ISO-BIS axis. - Locate P in the matrix BIS and P MAP The values ​​of the data are used to define the patient's position (B) relative to the optimal anesthesia zone (OAZ) in the matrix; - Provides an algorithm residing in the processing unit, configured to quantify the deviation of the patient position (B) relative to the optimal anesthesia zone (OAZ), and transforms the deviation into a quantitative change in the initial hypnotic concentration and initial analgesic concentration of the first anesthetic composition to define the target hypnotic concentration and target analgesic concentration of the second anesthetic composition; - Use the algorithm described above to process the patient's P. BIS and P MAP Data, to obtain the target hypnotic concentration and target anesthetic concentration of the second anesthetic composition, for treating the patient's P BIS and P MAP The data processing steps include the following sub-steps: - The deviation of the patient's position (B) from the point (A) of the optimal anesthesia zone (OAZ) is quantified using vector calculations. The sub-steps for quantification include the following: - Define the point (A) passing through the optimal anesthesia zone (OAZ), the vector (V) passing through the patient's position (B), and - Calculate the percentage deviation (D%) of the patient position (B) relative to the point (A) of the optimal anesthesia zone (OAZ) at the point of maximum deviation (C) of the MAP and BIS values ​​along the vector (V). - The deviation of the patient's position (B) relative to the point (A) of the optimal anesthesia zone (OAZ) is decomposed into the hypnotic deviation (D) relative to the point (A) of the optimal anesthesia zone (OAZ). H ) and / or analgesia deviation (D S ),as well as -Based on the hypnotic bias (D) H The increase or decrease in the initial hypnotic concentration of the first anesthetic composition is calculated based on the analgesic deviation (D). S The calculation is performed to determine whether the initial analgesic concentration of the first anesthetic composition has increased or decreased. This sub-step for the calculation includes the following sub-steps: - If the percentage deviation (D%) of the patient's position (B) relative to the point (A) of the optimal anesthesia zone (OAZ) is greater than 10%, modify the concentrations of hypnotics and analgesics; - The algorithm is used to generate a baseline related to the target hypnotic and analgesic concentrations of the second anesthetic composition, the baseline being configured to cause the processing unit (101) to generate a receptive signal for a graphical interface device (102) and / or a machine (103), the graphical interface device (102) being configured to display the target hypnotic and sedative concentrations processed by the algorithm, and the machine (103) being configured to deliver one or more drugs.

2. The method according to claim 1, wherein, The steps for defining the optimal anesthesia zone (OAZ) include: positioning the optimal anesthesia zone (OAZ) at a MAP value of 65 to 85 mmHg and a BIS value of 40 to 60.

3. The method according to claim 1 or 2, wherein, The matrix is ​​defined by the MAP variation from 0 to 150 mmHg and the BIS variation from 0 to 100, wherein the MAP dimension and the BIS dimension intersect each other orthogonally at the zero point (0; 0).

4. The method according to claim 1 or 2, wherein, Point (A) is defined by the intersection of the ISO-MAP axis at a MAP value of 75 mmHg and the ISO-BIS axis at a BIS value of 50.

5. The method according to claim 1 or 2, wherein, The percentage deviation (D%) of the patient's location (B) relative to the point (A) of the optimal anesthesia zone (OAZ) along the maximum deviation (C) of the MAP and BIS values ​​along the vector (V) is obtained using the following expression: 。 6. The method according to claim 1 or 2, wherein, The sub-steps for resolving the deviation of the patient position (B) relative to the point (A) of the optimal anesthesia zone (OAZ) include the following sub-steps: Hypnotic deviation (D) is calculated by applying the percentage deviation (D%) of the patient's position (B) relative to the point (A) of the optimal anesthesia zone (OAZ) to the hypnotic coefficient (H'). H The hypnotic coefficient (H') is obtained by dividing the hypnotic vector component (H) by the sum of the hypnotic vector component (H) and the analgesic vector component (S), wherein the hypnotic vector component (H) is measured as the distance between the patient position (B) and the ISO-BIS axis, and the analgesic vector component (S) is measured as the distance between the patient position (B) and the ISO-MAP axis.

7. The method according to claim 1 or 2, wherein, The sub-steps used to calculate the increase or decrease in the initial concentration of hypnotics and / or analgesics include the following sub-steps: -In the hypnotic deviation (D H If the concentration of the hypnotic drug is greater than 7.5%, the concentration should be changed; and -In the analgesia deviation (D S If the concentration is greater than 7.5%, change the analgesic concentration.

8. The method according to claim 1 or 2, wherein, The sub-steps used to calculate the increase or decrease in the initial concentration of hypnotics and / or analgesics include the following sub-steps: - The percentage deviation (D%) between the patient position (B) and the point (A) of the optimal anesthesia zone (OAZ) is greater than 10%, and at the same time, the hypnotic deviation (D) H If the concentration is greater than 7.5%, adjust the hypnotic drug concentration; - The percentage deviation (D%) between the patient position (B) and the point (A) of the optimal anesthesia zone (OAZ) is greater than 10%, and at the same time, the analgesia deviation (D) S If the concentration of analgesics is greater than 7.5%, the concentration of analgesics should be adjusted.

9. The method according to claim 1 or 2, wherein, The following expression is used to obtain the value based on the deviation (D). H ;D S The increase in the initial concentrations of hypnotic and analgesic in the first anesthetic composition: 。 10. The method according to claim 1 or 2, wherein, The following expression is used to obtain the value based on the deviation (D). H ;D S The reduction in the initial concentrations of hypnotic and analgesic in the first anesthetic composition: 。 11. The method according to claim 1 or 2, further comprising the step of: - Using the processing unit (101), a signal is generated based on the reference related to the concentrations of the target hypnotic drug and analgesic, and the signal is sent to a graphical interface device (102) configured to display the concentrations of the target hypnotic drug and sedative drug processed by the algorithm; and / or - Using the processing unit (101), a signal is generated based on the benchmark related to the concentration of the target hypnotic drug and analgesic, and the signal is sent to a machine (103) configured to deliver one or more drugs based on the concentration of the target hypnotic drug and sedative drug processed by the algorithm.

12. The method of claim 11, further comprising the step of: An anesthesiologist uses a graphical interface to approve benchmarks related to the target hypnotic and analgesic concentrations of the second anesthetic composition.

13. A computer program product comprising a computer program, wherein, The computer program is configured to perform the method according to any one of claims 1 to 11 when executed by a computer.

14. A PID controller configured to implement the method according to any one of claims 1 to 11.

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